Fax: (713) 794-4385
Central nervous system metastases in patients with high-risk breast carcinoma after multimodality treatment†
Article first published online: 27 AUG 2004
Copyright © 2004 American Cancer Society
Volume 101, Issue 8, pages 1760–1766, 15 October 2004
How to Cite
Gonzalez-Angulo, A. M., Cristofanilli, M., Strom, E. A., Buzdar, A. U., Kau, S.-W., Broglio, K. R., Smith, T. L. and Hortobagyi, G. N. (2004), Central nervous system metastases in patients with high-risk breast carcinoma after multimodality treatment. Cancer, 101: 1760–1766. doi: 10.1002/cncr.20530
Presented in part as a poster at the 86th Annual Meeting of the American Radium Society, Napa, CA, May 1–5, 2004.
- Issue published online: 1 OCT 2004
- Article first published online: 27 AUG 2004
- Manuscript Revised: 22 JUN 2004
- Manuscript Accepted: 22 JUN 2004
- Manuscript Received: 29 APR 2004
- Nellie B. Connally Breast Cancer Research Fund
- Susan G. Komen Multidisciplinary Breast Cancer Fellowship
- locally advanced breast carcinoma;
- inflammatory breast carcinoma;
- central nervous system metastases;
- primary chemotherapy
The current study was performed to determine the incidence of central nervous system (CNS) metastases and to examine associated disease characteristics in a group of patients with locally advanced breast carcinoma (LABC) or inflammatory breast carcinoma (IBC) treated at The University of Texas M. D. Anderson Cancer Center (Houston, TX).
Seven hundred sixty-eight patients treated with multimodality therapy between 1982 and 2000 in any of 6 neoadjuvant trials were eligible for the current study. Five hundred ninety-two patients (77%) had LABC, and 176 (23%) had IBC. CNS disease was defined as the presence of brain metastases or leptomeningeal disease. Time to detection of CNS disease and overall survival were estimated using the Kaplan–Meier product-limit method, and differences were evaluated using log-rank tests.
The median patient age was 48 years. Most tumors were classified as T4 lesions (58%) and exhibited lymph node involvement (78%). Fifty-one percent of all tumors had positive hormone receptor status. At a median follow-up duration of 9.5 years, 61 patients (8%) had developed CNS metastases, with the CNS representing the first site of recurrence for 38 of these 61 (63%). Characteristics associated with the development of CNS metastases over time included negative hormone receptor status (P = 0.03), Grade 3 disease (P = 0.01), and larger tumor size (P = 0.02). The median time to detection of CNS metastases was 2.3 years. Ten patients (16%) remained alive after treatment for CNS metastases. The median survival from the time of diagnosis of CNS metastases was 8 months.
CNS metastases from breast carcinoma were relatively uncommon and were strongly associated with more aggressive clinical presentation. Survival from the time of diagnosis of such metastases generally was short. Cancer 2004. © 2004 American Cancer Society.
Central nervous system (CNS) metastasis is one of the most serious complications in patients with systemic malignancies. Breast carcinoma is the second most common cause of brain metastases, which occur in approximately 10–15% of patients with breast disease,1 although autopsy data suggest that the actual figure may be as high as 30%.2 Identification of the CNS as the first metastatic site has become increasingly common in patients with breast carcinoma, due to the introduction of more sensitive and accurate diagnostic methods, the development of improved adjuvant and palliative therapy regimens, and improvements in survival.3–6 Furthermore, recent studies have reported that the CNS is now also identified as the first site of progression in many patients with controlled systemic disease.5, 7, 8
It is extremely uncommon for patients with primary breast carcinoma to show signs of CNS metastasis at the time of diagnosis. The median interval between the date of primary tumor diagnosis and the development of CNS involvement has been reported to be approximately 34 months.1, 9 Because of the relatively low incidence of CNS metastases, standard follow-up programs do not include routine brain imaging unless symptoms are present.
Over the past 20 years, patients with nonmetastatic locally advanced breast carcinoma (LABC) and patients with inflammatory breast carcinoma (IBC) have been treated at The University of Texas M. D. Anderson Cancer Center (MDACC; Houston, TX) using a multidisciplinary approach that includes neoadjuvant chemotherapy, surgery, systemic adjuvant chemotherapy, hormonal therapy, and locoregional radiotherapy. In the current study, we reviewed this group of patients with high-risk breast carcinoma to assess the prevalence and patterns of CNS recurrence as well as to identify the patient- and tumor-related characteristics associated with this type of recurrence.
MATERIALS AND METHODS
The current retrospective study included 775 patients with either LABC or IBC who had participated in any of 7 consecutive prospective neoadjuvant chemotherapy trials conducted at MDACC between 1982 and 2000.10–12 Sixteen percent of all patients with LABC had large Stage II tumors that prevented them from receiving primary surgery. Seven patients were excluded from the analysis because no information regarding the site of disease recurrence was available, leaving 768 patients for the analysis. The institutional review board (IRB) at the MDACC approved the individual clinical trials, and written informed consent was obtained from all participants before enrollment in these trials. The IRB also approved our retrospective review of the medical records for the purposes of the current study.
Breast carcinoma diagnosis was made via core-needle biopsy of the breast tumor. All pathologic specimens were reviewed by breast pathologists at MDACC. Histologic tumor types were defined according to the World Health Organization classification system,13 and histologic grade was assessed using the modified Black nuclear grading system.14 Immunohistochemical analysis of estrogen receptor (ER) and progesterone receptor (PR) status was performed using 4 μm sections of paraffin-embedded tissue specimens stained with the following monoclonal antibodies: 6F11 (Novocastra, Burlingame, CA) (for ER) and 1A6 (Novocastra) (for PR). Before 1993, the dextran-coated charcoal ligand-binding method was used to determine ER and/or PR status. The finding of nuclear staining in ≥ 10% of all cells was considered a positive result. A pathologic complete response (pCR) was defined as the absence of evidence of invasive carcinoma in the breast and in the axillary lymph nodes.
All patients investigated had received anthracycline-based neoadjuvant chemotherapy: 308 (40%) had received 3–4 cycles of vincristine 1 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 intravenously (i.v.) on Day 1 and prednisone 100 mg/m2 orally on Days 1–5 of treatment; and 460 (60%) had received 4 cycles of 5-fluorouracil 500 mg/m2 i.v. on Days 1 and 4, doxorubicin 50 mg/m2 i.v. via continuous infusion over 72 hours on Days 1–3, and cyclophosphamide 500 mg/m2 i.v. on Day 1. Eighteen patients with IBC had also received weekly paclitaxel (175–250 mg/m2 i.v. on Day 1, which subsequently was reduced to 80 mg/m2 i.v. on Day 1, every week for 12 weeks) as a part of primary chemotherapy in randomized clinical trials. Breast surgery generally consisted of total mastectomy until 1989, with segmental mastectomy, when permitted by tumor size according to the judgment of the multidisciplinary care team, being the preferred method thereafter. All patients with multifocal disease had undergone mastectomy. Axillary lymph node dissection had been performed in 761 patients (99%). Three hundred thirteen patients (41%), all with positive hormone receptor status, had received adjuvant tamoxifen for 5 years, and all 768 patients had received radiotherapy at the completion of primary chemotherapy and after surgery.
CNS metastasis was defined as the presence of metastatic disease in the brain and/or the presence of leptomeningeal disease. The diagnosis was made either via imaging studies (magnetic resonance or computed tomography) or via cytologic analysis of the cerebrospinal fluid.
We characterized our patient population by tabulating data on categoric variables, and we used event charts to display the pattern and timing of diagnosis, local and distant disease recurrence, CNS metastasis, and most recent follow-up. If an event, such as local disease recurrence or distant metastasis, occurred frequently within a particular time interval, either before or after CNS metastases, then this pattern would be apparent from the event chart.
The CNS metastasis–free survival duration and the duration of survival from the time of identification of the CNS as the first site of disease recurrence were estimated using the Kaplan–Meier product-limit method. We first measured the number of years of CNS metastasis–free survival from the date of diagnosis to the date of detection of CNS metastases or to the date of last follow-up; patients who died without detection of CNS involvement were censored at the date of death. Then, using a second approach, only CNS metastases that represented patients' first recurrences were counted as events, and survival measurements were censored at the date of first disease recurrence at any other site, death, or last follow-up. We used the log-rank test to evaluate associations between pretreatment variables and time to development of CNS metastases. Finally, we stratified first disease recurrences by site and computed the median survival duration associated with each site of first recurrence.
Statistical analyses were performed using SAS (Version 8; SAS Institute, Cary, NC) and S-Plus (Version 6.1; Insightful Corporation, Seattle, WA) software.
Seven hundred sixty-eight patients with diagnoses of high-risk breast carcinoma (LABC or IBC) who were treated in clinical trials at the MDACC between 1982 and 2000 were included in the current retrospective study. Of these patients, 592 (77%) had been treated for LABC, and 176 (23%) had been treated for IBC. The median follow-up duration for all patients was 9.5 years. There were 385 cases of disease recurrence and 322 deaths.
Sixty-one (8%) patients had developed CNS metastases, which represented the first disease recurrence in 38 of these cases (5%). CNS metastases presented as brain parenchymal disease in 40 patients (66%), as leptomeningeal disease in 12 patients (20%), and as both of these types of disease in 9 patients (14%).
Table 1 summarizes selected pretreatment characteristics of the study population. Approximately one-half of all patients (54%) were younger than age 50 years. In addition, 35% of all patients had ER-positive disease, and 44% of patients were without lymphovascular invasion (LVI). Each of the following disease characteristics was found in more than one-half of the study population: nuclear Grade 3 (60%), T3 or T4 status (82%), axillary lymph node involvement (78%), and Stage IIIA–IIIC (61%).
|Characteristic||No. of patients (%)|
|< 50||415 (54)|
|≥ 50||353 (46)|
|Estrogen receptor status|
|Progesterone receptor status|
|Modified nuclear grade|
|Lymph node status|
Figures 1 and 2, respectively, summarize the occurrence of major disease events over time for the 46 patients with LABC and the 18 patients with IBC who developed CNS disease. The event charts in Figures 1 and 2 show the time of diagnosis of the primary tumor, the time of diagnosis of locoregional disease recurrence, the time of diagnosis of distant metastases, the time of diagnosis of CNS metastases, and the time of death or last follow-up. These event histories are aligned with respect to the time of diagnosis of CNS metastases. Several patients, including some without any intervening disease recurrences, had been followed for > 5 years before developing CNS metastases. The median time to development of CNS metastases in all patients was 2.3 years. The event charts indicate that distant metastasis at another site was a more common event in these patients than was local disease recurrence. In most cases, the diagnosis of distant metastases at another site was made before or at the same time as the diagnosis of CNS metastases.
Table 2 shows Kaplan–Meier estimates of the probability of CNS metastasis–free survival in all patients at 5 years after diagnosis according to patient and tumor characteristics. The Kaplan–Meier estimate of the probability of CNS metastasis–free survival at 5 years was approximately 92%. Characteristics that were significantly associated with more aggressive disease tended to also be correlated with shorter times to development of CNS metastases. These characteristics included negative hormone receptor status (P = 0.03), nuclear Grade 3 (P = 0.01), larger tumor size (T3 or T4; P = 0.02), positive lymph node status (P = 0.01), and higher disease stage (IIIB or IIIC; P = 0.01). The presence of LVI and the absence of pCR were not found to be associated with CNS events.
|Characteristic||No. of patients||5 yr CNS metastasis–free rate (%)||Log-rank P value|
|Estrogen receptor/progesterone receptor status|
|Either one positive||17||95|
|Modified nuclear grade|
|Lymph node status|
All patients with CNS metastases as their first type of disease recurrence tended to have similar results. Negative hormone receptor status, nuclear Grade 3, positive lymph node status, and higher disease stage all were significantly associated with time to CNS metastasis for such patients. In addition, positive hormone receptor status and the absence of axillary lymph node involvement both were associated with longer CNS metastasis–free intervals in this subpopulation.
As indicated in the event charts, overall survival after the development of CNS metastases tended to be short. Table 3 shows the estimated median survival times after the first observation of evidence of disease recurrence at any site, with patients categorized by site of recurrence. Patients for whom bone was the lone site of first disease recurrence had the longest subsequent survival time, with a median of 22.4 months. Visceral sites were the most common sites of first recurrence, and subsequent survival times tended to be short for patients with visceral first recurrences (median, 11 months). Of the 38 patients with CNS metastases as their first type of disease recurrence, 6 had had concurrent visceral metastases; for these patients, the median survival duration from the time of disease recurrence was 8 months.
|Dominant site of first disease recurrence||No. of patients||No. of deaths||Estimated median survival (mos)|
|Soft tissue only||100||85||16.2|
|Central nervous system||38||33||8.1|
Of the 768 patients in the current study, 411 were alive as of most recent follow-up, including 10 of 61 patients with CNS metastases and 5 of 38 patients with CNS metastases as their first type of disease recurrence. Therapy for CNS metastases consisted of surgery followed by whole-brain irradiation (WBI) for 15 patients, surgery followed by intrathecal chemotherapy for 1 patient, WBI only for 35 patients, WBI followed by intrathecal chemotherapy for 3 patients, and intrathecal chemotherapy only for 4 patients. The remaining three patients declined treatment. Of the 10 patients who were alive at the start of the current study, 9 had undergone resection of their brain lesions and received WBI after recovering from surgery.
The current retrospective review examined the incidence of CNS metastases in a group of patients with high-risk breast carcinoma and identified patient and tumor characteristics that were significantly correlated with the development of these metastases.
CNS recurrence is not considered to be a common follow-up finding in patients with breast carcinoma. Several prognostic factors associated with this type of disease recurrence have been identified. It appears that CNS metastases tend to develop in younger patients who have larger tumors with more aggressive histologic features.15 Clinical and autopsy data show that the median age of patients who develop CNS metastases is 5 years younger than that of patients with breast carcinoma metastatic to other sites.1, 2, 16 In addition, ER-negative tumors are more likely to disseminate to the CNS.17, 18 Finally, Crivellari et al.4 reported the overexpression of HER-2/neu in 87% of patients with CNS metastases after treatment with epirubicin and docetaxel for LABC.4
The 8% incidence of CNS metastases in the current group of patients with high-risk breast carcinoma appears to be no greater than the corresponding rate for the overall population of individuals with breast carcinoma.1, 16 CNS metastasis–free survival duration was longer for patients with tumors that expressed hormone receptors, had lower nuclear grade, and presented as Stage II disease, perhaps indicating a subclinical spread in patients with more advanced disease and more aggressive histologic features. Unfortunately, a lack of data on HER-2/neu status prevented evaluation of the role of this marker in the study population. There was no increase in the incidence of CNS metastases in the current cohort compared with patients assessed in previous years. This low rate of incidence does not justify the modification of posttreatment surveillance guidelines.
In the past, only a limited number of patients with breast carcinoma had CNS metastases as their first type of disease recurrence.19 In recent years, however, significant improvements in systemic treatment appear to have led to an increase in the incidence of this type of disease recurrence16, 20; in particular, treatment regimens involving taxanes4, 7, 21 and/or trastuzumab22, 23 appear to be especially responsible for this increase in incidence.
The lung has been described as the most frequently involved distant site associated with CNS metastases in patients with breast carcinoma.16, 24 For 38 patients in the current study (62%), the CNS was the first site of disease recurrence, and all members of the study cohort had received some type of anthracycline-based therapy; this finding is consistent with the reports of other investigators.7, 20 Twenty-nine of the 61 patients with CNS metastases had other involved systemic sites. Of these 29 patients, 15 (52%) had lung involvement, whereas 12 (41%) had bone metastases. Statistical analysis failed to reveal any patient or tumor characteristics that were associated with a high risk of developing CNS metastases.
The survival duration for patients with breast carcinoma who die with CNS metastases is approximately 6 months shorter than the survival duration for patients with other sites of systemic recurrence.2 According to one study, patients with CNS involvement have a median survival of 6 months.25 The corresponding median survival reported in the current study was 8 months. (Because the median survival for all patients with metastatic breast carcinoma has increased in recent years and exceeds 2 years in the current series,26 a median survival of 8 months corresponds to a reduction of two-thirds in survival duration.)
Patients with other types of solid tumors typically die of extensive systemic disease, whereas approximately 50% of all patients with breast carcinoma who have CNS metastases die of neurologic complications exclusively.1, 27, 28 Patients with limited CNS disease who undergo surgical resection followed by radiotherapy may have more favorable outcomes.29–31 New diagnostic technologies and improvements in the palliative care of patients with metastatic breast carcinoma may contribute to the early identification of at-risk patients and lead to more effective treatment. There has been limited progress in the management of CNS metastases associated with breast carcinoma and other solid tumors. Patients with single or few brain metastases fare better when treated with both surgical resection and radiotherapy, and many patients can be appropriately treated with radiosurgery/gamma knife surgery. Nonetheless, WBI is the only treatment available for the majority of patients with CNS metastases, and the prognosis for patients with leptomeningeal disease remains as poor as it has been for several decades.93
- 6Central nervous system (CNS) metastases in women who receive trastuzumab for metastatic breast cancer (MBC) [abstract]. Proc Am Soc Clin Oncol. 2002; 21: 55a., , , et al.
- 10Response to induction chemotherapy for breast cancer: a prospective multimodality treatment program [abstract]. Proc Am Soc Clin Oncol. 1992; 11: 82., , .
- 11A Phase III randomized trial of dose-intensive neoadjuvant 5FU, doxorubicin, cyclophosphamide (FAC) with G-CSF (filgrastim) in locally advanced breast cancer (LABC). Efficacy and safety data [abstract]. Proc Am Soc Clin Oncol. 1999; 18: 74a., , , et al.
- 12Comparison of two adjuvant chemotherapy programs for locally advanced breast cancer: a prospective randomized trial [abstract]. Proc Am Soc Clin Oncol. 1990; 9: 21., , , et al.
- 21The impact of new chemotherapeutic and hormonal agents on the survival of women with metastatic breast cancer (MBC) in a population based cohort [abstract]. Proc Am Soc Clin Oncol. 2003; 22: 6., , , et al.
- 22Increased brain metastasis detected in metastatic breast cancer patients receiving herceptin [abstract]. Breast Cancer Res Treat. 2001; 69: 271., , , et al.
- 23A prognostic model to predict the risk of developing brain metastasis in patients treated with trastuzumab for HER-2 positive metastatic breast cancer [abstract]. Breast Cancer Res Treat. 2003; 82: 271., , , et al.